Skip to main content
Key Specialties
Cardiology Diabetology Endocrinology Gastroenterology Geriatrics and Gerontology Gynecology and Obstetrics Hematology Infectious Disease Internal Medicine Nephrology Neurology Oncology Pediatrics Respiratory Medicine Rheumatology Surgery
Congress Coverage
2024 ACC Congress 2023 ESMO Congress 2023 EASD Congress 2023 ERS Congress 2023 ESC Congress
Clinical Collections
Advances in Alzheimer’s

At a glance: The STEP trials

A round-up of the STEP phase 3 clinical trials evaluating semaglutide for weight loss in people with overweight or obesity.
ADVANCED SEARCH
Log in
Top
Journal of Neuroinflammation
Published in: Journal of Neuroinflammation 1/2016

Open Access 01-12-2016 | Research

Resveratrol suppresses glial activation and alleviates trigeminal neuralgia via activation of AMPK

Authors: Yan-jing Yang, Liang Hu, Ye-peng Xia, Chun-yi Jiang, Chen Miao, Chun-qing Yang, Miao Yuan, Lin Wang

Published in: Journal of Neuroinflammation | Issue 1/2016

Login to get access

Abstract

Background

Glial activation and neuroinflammation in the spinal trigeminal nucleus (STN) play a pivotal role in the genesis and maintenance of trigeminal neuralgia (TN). Resveratrol, a natural compound from grape and red wine, has a potential anti-inflammatory effect. We hypothesized that resveratrol could significantly suppress neuroinflammation in the STN mediated by glial activation and further relieve TN. In this study, we evaluated whether resveratrol could alleviate trigeminal allodynia and explore the mechanism underlying the antinociceptive effect of resveratrol.

Methods

Animals were orally injected with resveratrol after chronic constriction injury (CCI) of the infraorbital nerve. Mechanical thresholds of the affected whisker pad were measured to assess nociceptive behaviors. The STN was harvested to quantify the changing levels of p-NR1, p-PKC, TNF-α, and IL1-β by western blotting and detect the expression of calcitonin gene-related peptide (CGRP) and c-Fos by immunofluorescence. Glial activation was observed by immunofluorescence and western blotting. Mitogen-activated protein kinase (MAPK) phosphorylation in vivo and in vitro was examined by western blotting.

Results

We found that resveratrol significantly attenuated trigeminal allodynia dose-dependently and decreased the increased expression of CGRP and c-Fos in the STN. Additionally, resveratrol showed an inhibitory effect on CCI-evoked astrocyte and microglia activation and reduced production of pro-inflammatory cytokines in the STN. Furthermore, the antinociceptive effect of resveratrol was partially mediated by reduced phosphorylation of MAP kinases via adenosine monophosphate-activated protein kinase (AMPK) activation.

Conclusions

AMPK activation in the STN glia via resveratrol has utility in the treatment of CCI-induced neuroinflammation and further implicates AMPK as a novel target for the attenuation of trigeminal neuralgia.
Literature
1.
Cheshire WP. Trigeminal neuralgia: for one nerve a multitude of treatments. Expert Rev Neurother. 2007;7:1565–79.CrossRefPubMed
2.
Hokfelt T, Zhang X, Wiesenfeld-Hallin Z. Messenger plasticity in primary sensory neurons following axotomy and its functional implications. Trends Neurosci. 1994;17:22–30.CrossRefPubMed
3.
Alvares D, Fitzgerald M. Building blocks of pain: the regulation of key molecules in spinal sensory neurones during development and following peripheral axotomy. Pain. 1999;Suppl 6:S71-85.
4.
Dieb W, Hafidi A. Astrocytes are involved in trigeminal dynamic mechanical allodynia: potential role of D-serine. J Dent Res. 2013;92:808–13.CrossRefPubMed
5.
Shibuta K, Suzuki I, Shinoda M, Tsuboi Y, Honda K, Shimizu N, Sessle BJ, Iwata K. Organization of hyperactive microglial cells in trigeminal spinal subnucleus caudalis and upper cervical spinal cord associated with orofacial neuropathic pain. Brain Res. 2012;1451:74–86.CrossRefPubMed
6.
DeLeo JA, Yezierski RP. The role of neuroinflammation and neuroimmune activation in persistent pain. Pain. 2001;90:1–6.CrossRefPubMed
7.
Watkins LR, Milligan ED, Maier SF. Glial activation: a driving force for pathological pain. Trends Neurosci. 2001;24:450–5.CrossRefPubMed
8.
9.
10.
Moalem G, Tracey DJ. Immune and inflammatory mechanisms in neuropathic pain. Brain Res Rev. 2006;51:240–64.CrossRefPubMed
11.
Shamash S, Reichert F, Rotshenker S. The cytokine network of Wallerian degeneration: tumor necrosis factor-alpha, interleukin-1alpha, and interleukin-1beta. J Neurosci. 2002;22:3052–60.PubMed
12.
Okamoto K, Martin DP, Schmelzer JD, Mitsui Y, Low PA. Pro- and anti-inflammatory cytokine gene expression in rat sciatic nerve chronic constriction injury model of neuropathic pain. Exp Neurol. 2001;169:386–91.CrossRefPubMed
13.
Yu W, Fu YC, Wang W. Cellular and molecular effects of resveratrol in health and disease. J Cell Biochem. 2012;113:752–9.CrossRefPubMed
14.
Chu LM, Lassaletta AD, Robich MP, Sellke FW. Resveratrol in the prevention and treatment of coronary artery disease. Curr Atheroscler Rep. 2011;13:439–46.CrossRefPubMed
15.
Virgili M, Contestabile A. Partial neuroprotection of in vivo excitotoxic brain damage by chronic administration of the red wine antioxidant agent, trans-resveratrol in rats. Neurosci Lett. 2000;281:123–6.CrossRefPubMed
16.
Girbovan C, Morin L, Plamondon H. Repeated resveratrol administration confers lasting protection against neuronal damage but induces dose-related alterations of behavioral impairments after global ischemia. Behav Pharmacol. 2012;23:1–13.CrossRefPubMed
17.
Singleton RH, Yan HQ, Fellows-Mayle W, Dixon CE. Resveratrol attenuates behavioral impairments and reduces cortical and hippocampal loss in a rat controlled cortical impact model of traumatic brain injury. J Neurotrauma. 2010;27:1091–9.CrossRefPubMedPubMedCentral
18.
Ates O, Cayli S, Altinoz E, Gurses I, Yucel N, Kocak A, Yologlu S, Turkoz Y. Effects of resveratrol and methylprednisolone on biochemical, neurobehavioral and histopathological recovery after experimental spinal cord injury. Acta Pharmacol Sin. 2006;27:1317–25.CrossRefPubMed
19.
20.
Tillu DV, Melemedjian OK, Asiedu MN, Qu N, De Felice M, Dussor G, Price TJ. Resveratrol engages AMPK to attenuate ERK and mTOR signaling in sensory neurons and inhibits incision-induced acute and chronic pain. Mol Pain. 2012;8:5.CrossRefPubMedPubMedCentral
21.
Han Y, Jiang C, Tang J, Wang C, Wu P, Zhang G, Liu W, Jamangulova N, Wu X, Song X. Resveratrol reduces morphine tolerance by inhibiting microglial activation via AMPK signalling. Eur J Pain. 2014;18:1458.CrossRefPubMed
22.
Srinivasan D, Yen JH, Joseph DJ, Friedman W. Cell type-specific interleukin-1beta signaling in the CNS. J Neurosci. 2004;24:6482–8.CrossRefPubMed
23.
Xuan A, Long D, Li J, Ji W, Zhang M, Hong L, Liu J. Hydrogen sulfide attenuates spatial memory impairment and hippocampal neuroinflammation in beta-amyloid rat model of Alzheimer’s disease. J Neuroinflammation. 2012;9:202.CrossRefPubMedPubMedCentral
24.
Wang X, Loram LC, Ramos K, de Jesus AJ, Thomas J, Cheng K, Reddy A, Somogyi AA, Hutchinson MR, Watkins LR, Yin H. Morphine activates neuroinflammation in a manner parallel to endotoxin. Proc Natl Acad Sci U S A. 2012;109:6325–30.CrossRefPubMedPubMedCentral
25.
Blasi E, Barluzzi R, Bocchini V, Mazzolla R, Bistoni F. Immortalization of murine microglial cells by a v-raf/v-myc carrying retrovirus. J Neuroimmunol. 1990;27:229–37.CrossRefPubMed
26.
Henn A, Lund S, Hedtjarn M, Schrattenholz A, Porzgen P, Leist M. The suitability of BV2 cells as alternative model system for primary microglia cultures or for animal experiments examining brain inflammation. ALTEX. 2009;26:83–94.PubMed
27.
Vos BP, Strassman AM, Maciewicz RJ. Behavioral evidence of trigeminal neuropathic pain following chronic constriction injury to the rat’s infraorbital nerve. J Neurosci. 1994;14:2708–23.PubMed
28.
Zagami AS, Goadsby PJ, Edvinsson L. Stimulation of the superior sagittal sinus in the cat causes release of vasoactive peptides. Neuropeptides. 1990;16:69–75.CrossRefPubMed
29.
Michot B, Bourgoin S, Viguier F, Hamon M, Kayser V. Differential effects of calcitonin gene-related peptide receptor blockade by olcegepant on mechanical allodynia induced by ligation of the infraorbital nerve vs the sciatic nerve in the rat. Pain. 2012;153:1939–48.CrossRefPubMed
30.
Jaaskelainen SK. Clinical neurophysiology and quantitative sensory testing in the investigation of orofacial pain and sensory function. J Orofac Pain. 2004;18:85–107.PubMed
31.
Robinson PP, Boissonade FM, Loescher AR, Smith KG, Yates JM, Elcock C, Bird EV, Davies SL, Smith PL, Vora AR. Peripheral mechanisms for the initiation of pain following trigeminal nerve injury. J Orofac Pain. 2004;18:287–92.PubMed
32.
Truelove E. Management issues of neuropathic trigeminal pain from a dental perspective. J Orofac Pain. 2004;18:374–80.PubMed
33.
Zong Y, Sun L, Liu B, Deng YS, Zhan D, Chen YL, He Y, Liu J, Zhang ZJ, Sun J, Lu D. Resveratrol inhibits LPS-induced MAPKs activation via activation of the phosphatidylinositol 3-kinase pathway in murine RAW 264.7 macrophage cells. PLoS One. 2012;7:e44107.CrossRefPubMedPubMedCentral
34.
Jimenez-Diaz L, Geranton SM, Passmore GM, Leith JL, Fisher AS, Berliocchi L, Sivasubramaniam AK, Sheasby A, Lumb BM, Hunt SP. Local translation in primary afferent fibers regulates nociception. PLoS One. 2008;3:e1961.CrossRefPubMedPubMedCentral
35.
Huang HL, Cendan CM, Roza C, Okuse K, Cramer R, Timms JF, Wood JN. Proteomic profiling of neuromas reveals alterations in protein composition and local protein synthesis in hyper-excitable nerves. Mol Pain. 2008;4:33.CrossRefPubMedPubMedCentral
36.
Taves S, Berta T, Chen G, Ji RR. Microglia and spinal cord synaptic plasticity in persistent pain. Neural Plast. 2013;2013:753656.PubMedPubMedCentral
37.
38.
Rock RB, Peterson PK. Microglia as a pharmacological target in infectious and inflammatory diseases of the brain. J Neuroimmune Pharmacol. 2006;1:117–26.CrossRefPubMed
39.
Binshtok AM, Wang H, Zimmermann K, Amaya F, Vardeh D, Shi L,Brenner GJ, Ji RR, Bean BP, Woolf CJ, Samad TA. Nociceptors are interleukin-1beta sensors. J Neurosci. 2008;28:14062–73.CrossRefPubMedPubMedCentral
40.
Zhang Q, Yuan L, Zhang Q, Gao Y, Liu G, Xiu M, Wei X, Wang Z, Liu D. Resveratrol attenuates hypoxia-induced neurotoxicity through inhibiting microglial activation. Int Immunopharmacol. 2015;28:578–87.CrossRefPubMed
41.
Schafers M, Lee DH, Brors D, Yaksh TL, Sorkin LS. Increased sensitivity of injured and adjacent uninjured rat primary sensory neurons to exogenous tumor necrosis factor-alpha after spinal nerve ligation. J Neurosci. 2003;23:3028–38.PubMed
42.
Ohtori S, Takahashi K, Moriya H, Myers RR. TNF-alpha and TNF-alpha receptor type 1 upregulation in glia and neurons after peripheral nerve injury: studies in murine DRG and spinal cord. Spine (Phila Pa 1976). 2004;29:1082–8.CrossRef
43.
Hardie DG, Hawley SA. AMP-activated protein kinase: the energy charge hypothesis revisited. Bioessays. 2001;23:1112–9.CrossRefPubMed
44.
Hardie DG. AMP-activated protein kinase: a cellular energy sensor with a key role in metabolic disorders and in cancer. Biochem Soc Trans. 2011;39:1–13.CrossRefPubMed
45.
Zhang BB, Zhou G, Li C. AMPK: an emerging drug target for diabetes and the metabolic syndrome. Cell Metab. 2009;9:407–16.CrossRefPubMed
46.
Price TJ, Dussor G. AMPK: an emerging target for modification of injury-induced pain plasticity. Neurosci Lett. 2013;557 Pt A:9–18.CrossRefPubMed
47.
Melemedjian OK, Asiedu MN, Tillu DV, Sanoja R, Yan J, Lark A, Khoutorsky A, Johnson J, Peebles KA, Lepow T,et al. Targeting adenosine monophosphate-activated protein kinase (AMPK) in preclinical models reveals a potential mechanism for the treatment of neuropathic pain. Mol Pain. 2011;7:70.CrossRefPubMedPubMedCentral
48.
49.
Song H, Han Y, Pan C, Deng X, Dai W, Hu L, Jiang C, Yang Y, Cheng Z, Li F,et al. Activation of adenosine monophosphate-activated protein kinase suppresses neuroinflammation and ameliorates bone cancer pain: involvement of inhibition on mitogen-activated protein kinase. Anesthesiology. 2015;123:1170.CrossRefPubMed
50.
Maixner DW, Yan X, Gao M, Yadav R, Weng HR. Adenosine monophosphate-activated protein kinase regulates interleukin-1beta expression and glial glutamate transporter function in rodents with neuropathic pain. Anesthesiology. 2015;122:1401–13.CrossRefPubMed
51.
Wight RD, Tull CA, Deel MW, Stroope BL, Eubanks AG, Chavis JA, Drew PD, Hensley LL. Resveratrol effects on astrocyte function: relevance to neurodegenerative diseases. Biochem Biophys Res Commun. 2012;426:112–5.CrossRefPubMedPubMedCentral
52.
Zhang F, Wang H, Wu Q, Lu Y, Nie J, Xie X, Shi J. Resveratrol protects cortical neurons against microglia-mediated neuroinflammation. Phytother Res. 2013;27:344–9.CrossRefPubMed
53.
Shih MH, Kao SC, Wang W, Yaster M, Tao YX. Spinal cord NMDA receptor-mediated activation of mammalian target of rapamycin is required for the development and maintenance of bone cancer-induced pain hypersensitivities in rats. J Pain. 2012;13:338–49.CrossRefPubMedPubMedCentral
54.
55.
Katsura H, Obata K, Miyoshi K, Kondo T, Yamanaka H, Kobayashi K, Dai Y, Fukuoka T, Sakagami M, Noguchi K. Transforming growth factor-activated kinase 1 induced in spinal astrocytes contributes to mechanical hypersensitivity after nerve injury. Glia. 2008;56:723–33.CrossRefPubMed
56.
Johnson GL, Lapadat R. Mitogen-activated protein kinase pathways mediated by ERK, JNK, and p38 protein kinases. Science. 2002;298:1911–2.CrossRefPubMed
57.
Lee JC, Laydon JT, McDonnell PC, Gallagher TF, Kumar S, Green D, McNulty D, Blumenthal MJ, Heys JR, Landvatter SW, et al. A protein kinase involved in the regulation of inflammatory cytokine biosynthesis. Nature. 1994;372:739–46.CrossRefPubMed
58.
Porro C, Cianciulli A, Calvello R, Panaro MA. Reviewing the role of resveratrol as a natural modulator of microglial activities. Curr Pharm Des. 2015;21:5277–91.CrossRefPubMed
Metadata
Title
Resveratrol suppresses glial activation and alleviates trigeminal neuralgia via activation of AMPK
Authors
Yan-jing Yang
Liang Hu
Ye-peng Xia
Chun-yi Jiang
Chen Miao
Chun-qing Yang
Miao Yuan
Lin Wang
Publication date
01-12-2016
Publisher
BioMed Central
Published in
Journal of Neuroinflammation / Issue 1/2016
Electronic ISSN: 1742-2094
DOI
https://doi.org/10.1186/s12974-016-0550-6

Other articles of this Issue 1/2016

Journal of Neuroinflammation 1/2016 Go to the issue

Research

Glial cell activation, recruitment, and survival of B-lineage cells following MCMV brain infection

Research

PARP inhibition in leukocytes diminishes inflammation via effects on integrins/cytoskeleton and protects the blood-brain barrier

Research

Colony-stimulating factor 1 receptor blockade prevents fractionated whole-brain irradiation-induced memory deficits

Research

Cocaine-mediated induction of microglial activation involves the ER stress-TLR2 axis

Research

Interferon gamma protects neonatal neural stem/progenitor cells during measles virus infection of the brain

Research

Urban traffic-derived nanoparticulate matter reduces neurite outgrowth via TNFα in vitro